Project Summary The physiological relevance of brown adipose tissue in humans is largely unknown. We have shown that suppressing ovarian function in premenopausal women reduces resting energy expenditure (REE), and this is prevented by adding back estradiol (E2). Our preliminary data suggest that this may be due, in part, to reduced brown adipose tissue (BAT) activity. There is also compelling evidence from basic and pre-clinical studies that BAT function and thermogenic activity is modulated by E2. However, whether E2 status affects BAT activity in women has not been studied. Our overarching hypothesis is that BAT activity in humans is modulated by E2. In this research, we will study 1) the contribution of BAT to REE under basal (room temperature) and stimulated conditions (mild cold-exposure); and 2) whether these responses are modulated by E2 status. To determine if natural declines in endogenous E2 contribute to changes in BAT activity, we will compare BAT activity in pre- and post-menopausal women. We will also explore whether suppression of ovarian hormones in pre- menopausal women impairs BAT activity. BAT activity will be quantified using dynamic positron emission topography/computed tomography (PET/CT) imaging combined with 11C-acetate tracers. We will assess the thermogenic response of BAT by measuring cold-induced changes in REE, shivering, and skin and core temperature. The proposed research is well-aligned with two of the primary objectives of RFA-DK-15-031, which are 1) to explore the biological functions of BAT in humans; and 2) determine conditions that modulate its activity in humans. Studying E2-mediated effects on BAT and REE will increase our understanding of how the loss of ovarian function during the menopausal transition contributes to weight gain and an increase in visceral adipose tissue, increasing the risk of obesity-related chronic diseases. This could lead to development of behavioral or pharmacologic interventions to attenuate decreases in REE and reduce risk for weight gain.